Therapeutic agents can be introduced into a subject by several different routes. Most commonly, therapeutic agents are orally administered because it is a convenient, safe, and cost effective way to making the agent systemically available to the body. However, in many cases, oral administration is not preferred. For example, certain therapeutic agents are not stable in, or taken up into the body by the digestive tract. Therapeutic agents such as proteins, polypeptides, or oligopeptides (collectively referred to herein as “polypeptides”) are typically not orally administered.
Therapeutic polypeptides are typically administered by routes that avoid conditions that destroy the polypeptide, such as would occur with proteolysis in portions of the digestive tract. Commonly used injection routes for polypeptides include subcutaneous, intramuscular, and intravenous injections. Frequent injections are often necessary due to short plasma half-lives of polypeptides. In some cases, mucosal administration of polypeptides can be performed using methods that place the polypeptide in contact with membranes lining the urogenital or and respiratory tracts.
Many current therapeutic preparations of polypeptide therapeutics are liquid formulations (for example, liquid formulations of insulin), which are injected into a subject to provide a therapeutic effect. However, many of these injectable compositions provide a therapeutic response over a limited period of time.
Solid formulations of polypeptides have been prepared in attempt to lengthen the therapeutic window for polypeptide. One approach is to crush or grind lyophilized polypeptides into small particulates, which can be administered to a patient. This approach is less than desirable as it results in the formation of particulates substantially heterogenous in size and shapes. This approach can also be detrimental to the activity of the polypeptide if aggressive techniques are used to create the particulates.
Another approach for delivering polypeptides to a subject is to use polymer microparticles that are associated with polypeptides. Microparticles refer to those particles having a diameter of less than 1 mm, and are more typically found as having a diameter of less than 0.1 mm (100 μm). Most microparticles are spherical in shape (i.e., microspheres), although microparticles may be observed having other non-spherical shapes. Spray drying, phase separation, solvent evaporation, and emulsification are common techniques used to make microparticles, which are typically formed from synthetic or natural polymers. For purposes of drug delivery, microparticles made using these techniques can have desirable properties, such as size and uniformity. However, many microparticle preparations have low polypeptide content due the presence of a larger content of excipient polymer in the microparticle. This can significantly limit the amount of polypeptide that can become available to a subject upon administration of the microparticles.
The preparation of microparticles having a high polypeptide content, such as those composed predominantly or entirely of polypeptides, can be very challenging. Standard techniques may lead to polypeptide microparticle preparations that are highly amorphous and that do not resemble microparticles, substantially aggregated, non-dissolvable peptide particles, or highly cracked or fractured protein particles. Some techniques may not even form particles.
Another challenge involves the preparation of a batch (e.g., a “set”) of polypeptide microparticles that have low size polydispersity. A set of polypeptide microparticles polypeptide having a low size polydispersity tends to have fewer polypeptides microparticles in the set of a size that considerably deviate in size from the mean microparticle size of the set. Previous techniques, however, often provide microparticle sets with higher size dispersity, and there is no particularly good technique for removing microparticles from the set that are of sizes that substantially deviate from the mean size of the set. In applications of the present invention, it has been found desirable to produce sets of microparticles having low size polydispersity.
The present invention addresses challenges in the art of polypeptide microparticle preparation and provides improvements for the preparation of microparticles having desirable particle shape, particle morphology, polypeptide release and activity, and particle size dispersity.
The present invention also addresses challenges in the art of localized or site-specific delivery of bioactive agents, and allows for improvements in bioactive agent release rates and bioactive agent activity, which can generally provide improved treatment for subjects with particular medical conditions.